The long-term objectives of the project are to establish the site and mechanism of action of the two mutations diabetes (db) and obese (ob) that cause severe and rapidly developing diabetes-obesity syndromes in mice and to compare the metabolic alterations observed in these mutants with other single gene mutations that cause similar but milder obesity conditions. The specific aims of this application are to assess and define the mode of action of the adrenal androgen, dehydroepiandrosterone (DHEA) and its metabolites in producing the marked beneficial effects on both of these syndromes and to establish how much the deranged hormonal milieu associated with mutants contributes to increased metabolic efficiency by preventing normal metabolic turnover of tissue. Whether DHEA acts as a modulator that can restore a more normal hormonal balance will be assessed. The effects of the inbred background both on the expression of these syndromes and on the therapeutic effects of DHEA and its metabolites will be studied in the hopes of identifying specific genetic modifiers involved in the differing strain responses. An understanding of the mode of action of these new anti-diabetic agents and their interaction with different forms of genetic diabetes should provide new information regarding glucose homeostasis, factors regulating beta cell replication, and could provide data that would suggest the primary lesion in each syndrome. Once the most effect dosages and the toxicity are established, these new oral hypoglycemic agents may become significant in the treatment of human diabetes.